Objective: To evaluate the effectiveness of a program to reduce work-related musculoskeletal disorders (WRMSD) among surgeons. Background: Surgeons are at high risk of WRMSD due to many physical and psychosocial factors. Methods: This study is a multicenter randomized clinical trial (UMIN000028557) conducted from January to August 2015. Following cluster randomization by surgical division, surgeons were allocated to 2 groups. The NPP group (No Preventive Program) underwent no intervention, while the PP group (Preventive Program) followed ergonomic principles in the operating room and specific physical exercises supervised by a physical therapist. A multiple logistic regression was performed to identify baseline WRMSD risk factors. WRMSD assessment was based on 1 ad hoc and 3 validated questionnaires: Nordic Musculoskeletal Questionnaire (NMQ), Numerical Rating Scale (NRS), and Short Form 36 Health Survey (SF-36). Follow-up was planned after 3 and 6 months. Results: One hundred forty-one surgeons matched the inclusion criteria and were randomized in the PP (n = 65) and NPP (n = 76) groups. At the initial analysis, physical activity was the only modifiable independent risk factor for WRMSD (OR, 2.44; P = 0.05). The PP group showed a significant improvement in the item “General Health” (GH) regarding quality of life at 3 (NPP: 70.5 ± 15.2 vs PP: 75.9 ± 14.1; P = 0.04) and 6 months (70.6 ± 13.4 vs 75.3 ± 13.0; P = 0.04). The PP group had a significant reduction of low back pain (66.2% vs 50.0%; P = 0.04) and analgesic consumption (30.9% vs 15.5%; P = 0.03) after 6 months. Conclusions: This study demonstrated the effectiveness of a global program based on the application of ergonomics in the operating room and specific physical exercises.